2,5-Bis [4-O-methoxyamidinophenyl] furan, which has the structure
is a prodrug of furamidine, and is effective when administered orally in an immunosupressed rat model for Pneumocystis carinii pneumonia (PCP). It is also effective against mouse models of human African trypanosomiasis (Boykin et al., (1996) Bioorg. Med. Chem. Lett. 6:3017; Tidwell & Boykin, in Small Molecule DNA and RNA Binders: From Synthesis to Nucleic Acid Complexes (Demeunynck et al., eds.) Wiley-VCH, New York, 2002). Compound 1 is currently in Phase II clinical trials against both of these diseases (Tidwell & Boykin, in Small Molecule DNA and RNA Binders: From Synthesis to Nucleic Acid Complexes (Demeunynck et al., eds.) Wiley-VCH, New York, 2002). It has been shown that 2,5-bis [4-O-methoxyamidinophenyl] furan (Compound 1) and 2,5-bis [4-hydroxyamidinophenyl] furan, which has the chemical structure
were approximately equally effective against PCP when administered orally. However, the closely related analog 2,5-bis [4-O-ethoxyamidinophenyl] furan, which has the structure
was not effective (Boykin et al., (1996) Bioorg. Med. Chem. Lett. 6:3017).
The prior synthesis of Compound 1 and analogs involved the reaction of 2,5-bis [4-cyanophenyl] furan under Pinner-type conditions to form the corresponding imidate ester, which was then allowed to react with the appropriate hydroxylamine (Boykin et al., (1996) Bioorg. Med. Chem. Lett. 6:3017). The Pinner process (Pinner, (1883) Chem. Ber. 16:1643–1655; see also Walz et al., (1977) Macromol. Chem. 178:2527–2534) is cumbersome, since rigorous exclusion of water is essential. When the Pinner process is employed to prepare Compound 1 and related compounds, the process is further complicated due to the very low solubility of 2,5-bis [4-cyanophenyl] furan, necessitating long reaction times, on the order of 3–7 days.
Thus, what is needed is a method of synthesizing bis-heteroaryl compounds, such as 2,5-bis [4-hydroxy and 4-O-alkylamidinophenyl] furans having the general structure
that is simple and economical, and that avoids the drawbacks of the Pinner process. The methods of the present invention address these and other needs in the art.